The FDA outlined concerns of overtreatment in AstraZeneca’s clinical trial of its immune checkpoint drug before and after lung cancer surgery ahead of a public panel with outside experts on Thursday.
The drug regulator plans to ask its advisory committee to discuss whether the company should run another trial for Imfinzi, as well as whether future trials of perioperative regimens — treatments given before and after surgery to remove cancer — should be required to look at the contribution of each part of the treatment.
The FDA’s primary problem with AstraZeneca’s study is that it fails to distinguish the benefit from giving Imfinzi before surgery from that of giving it after surgery, according to briefing documents posted by the agency Tuesday morning.
Emerging data from clinical trials don’t necessarily suggest more immunotherapy around surgery leads to substantially better outcomes, raising “concern for potential overtreatment and its attendant toxicities,” according to the FDA.
The AstraZeneca study in question — AEGEAN — showed that Imfinzi and chemotherapy around lung cancer surgery improved event-free survival compared to placebo and chemotherapy around surgery. Patients with stage 2a to 3b cancer in the treatment arm received Imfinzi plus chemotherapy before surgery, followed by Imfinzi alone after surgery for up to a year.
“Particularly concerning is the additional year of adjuvant treatment if exposure to ICI and its toxicities does not add additional efficacy to neoadjuvant chemoimmunotherapy,” the FDA wrote. Adjuvant treatment refers to therapies given after surgery, while neoadjuvant refers to those given before.
Other immune checkpoint drugs have been approved for use around lung cancer surgery already, including perioperative Keytruda. Bristol Myers Squibb is also waiting for an FDA decision by Oct. 8 on perioperative Opdivo in similar stages of lung cancer.
Top cancer drug regulators from the US and Europe, including FDA’s Rick Pazdur, have previously voiced concerns about overtreatment with immunotherapy in early-stage cancer patients.
At interim analysis, AstraZeneca’s study has yet to show an overall survival benefit, considered a gold standard by cancer doctors.
“Even if a statistically significant improvement in OS is eventually demonstrated in the AEGEAN trial, the inability to demonstrate contribution of phase would remain problematic,” the agency wrote.
Notably, the FDA also said that it previously recommended AstraZeneca, as well as other drug developers, to design studies that discern the contributions of each portion of treatment, but “sponsors have not heeded this advice.”
In 2018, the FDA told AstraZeneca that its trial design “would not isolate the effect of the treatment phases and recommended that the Applicant should consider a factorial study design,” a position the agency reiterated in 2023.
“Intensification of perioperative add-on designs only exacerbates concerns for overtreatment. To address the issue of contribution of treatment phase, alternative trial designs are increasingly necessary to evaluate the efficacy of novel drugs in each treatment phase of a perioperative regimen,” the agency wrote.